Hepatic lipase plays an important role in lipid metabolism. Hepatic lipase is a glycoprotein that functions as a ligand or as an enzyme of approximately 65 Kda, which has been shown to catalyze the hydrolysis of lipids including triglycerides, diglycerides and phospholipids in native lipoproteins. It has also been shown to facilitate the selective uptake of cholesterol from high-density lipoproteins and the removal of remnant particles by the liver (Jonathan C. Cohen, et al Biochemistry 1992, 31: 8544-8551 and Neve et al Biochemistry J. 1998, 330:701-706).
Other studies showing the inverse relationship of HDL and hepatic lipase activity include for example, Haffner S. M. et al., “Studies on the metabolic mechanism of reduced high density lipoproteins during anabolic steroid therapy,” Metabolism 1983; 32:413-420; Applebaum-Bowden D, et al., “The Dyslipoproteinemia of Anabolic steroid therapy: increase in hepatic triglyceride lipase precedes the decrease in high density lipoprotein-2 cholesterol,” Metabolism 1987; 36:949-952; and Kantor M. A. et al., “Androgens reduce HDL-2 cholesterol and increase hepatic triglyceride lipase activity,” Med. Sci. Sport exercise 1985; 17:462-465.
The inverse relationship between hepatic lipase activity and the level of HDL-cholesterol, particularly type-2 HDL-cholesterol, can be used to advantage in up-regulating the Level of HDL cholesterol-the good cholesterol.
Endothelial lipase (EL) is a newly described member of the lipase gene family. Like hepatic lipase, endothelial lipase has been implicated in the hydrolysis of HDL phospholipids and in the reduction of HDL-cholesterol in vivo.
In experiments using hepatic lipase knockout mice the infusion of a polyclonal antibody inhibitory to endothelial lipase resulted in a marked increase in HDL-cholesterol levels (Rader, D. J., et al Journal of Clinical Investigation (2003), 111(3) 357-362.
Chan, et al, Proceedings of the National Academy of Sciences U.S.A. (2003), 100(5), 2748-2753, has also reported the inverse relation between endothelial lipase and HDL-cholesterol.
Given the preceding information, it is desirable to discover and develop compounds that increase HDL levels by methods that may include inhibiting the activity of hepatic lipase and/or endothelial lipase in order to treat, prevent and/or ameliorate the effects of hepatic lipase and/or endothelial lipase mediated diseases. Few therapeutically desirable agents are available to accomplish the task of increasing HDL levels hence the need for and utility of the present invention.